Severe mammary fibroepithelial hyperplasia due to single injection of medroxyprogesterone acetate in two male cats / Hiperplasia fibroadenomatosa mamária felina secundária à aplicação única de acetato de medroxiprogesterona em dois felinos machos

Thirty and forty days after a 50 mg medroxyprogesterone acetate injection, respectively, two mixed-breed, 7 and 8-month-old entire male cats presented diffuse enlargement of thoracic and abdominal mammary glands, with ulceration, abscessation and necrosis. One patient was treated with 10 mg/kg aglepristone, antibiotic therapy, analgesic and non-steroidal anti-inflammatory compound; however a worse enlargement of mammary glands, necrosis and clinical condition was noted two days after antiprogestin injection. The second patient was submitted to surgical procedure without previous medical treatment. A partial bilateral mastectomy and conventional orchiectomy were performed, and both patients presented no clinical abnormalities 10 days after surgical treatment. In the male cat, the interruption of progesterone associated mammary fibroepithelial hyperplasia cannot be based in gonadectomy, being antiprogestin treatment the primary approach. Mastectomy can be a treatment option in selected cases, such as the two cases presented here, in case of antiprogestin treatment failure or in case of extensive ulceration, necrosis and risk of sepsis.(AU)

Trinta e quarenta dias após aplicação de acetato de medroxiprogesterona, dois gatos SRD machos não castrados, de sete e oito meses respectivamente, apresentaram aumento difuso de volume em glândulas mamárias torácicas e abdominais, com ulceração, abscedação e necrose. Um paciente foi tratado com 10 mg/kg de aglepristone, terapia antimicrobiana, analgésicos e anti-inflamatório não-esteroidal. Entretanto, apresentou piora dos sinais clínicos, da abscedação e necrose dois dias após a aplicação. O outro paciente foi submetido a procedimento cirúrgico sem tratamento clínico prévio. Mastectomia parcial bilateral e orquiectomia convencional foram realizadas e, ambos os pacientes se apresentaram sem alterações clínicas e receberam alta após 10 dias do procedimento cirúrgico. No felino macho, a interrupção da ação da progesterona associada à ocorrência de hiperplasia fibroadenomatosa mamária, não pode ser obtida por meio de gonadectomia, portanto, o tratamento de eleição deve ser realizado com utilização de antiprogestágeno. Em alguns casos, mastectomia parcial ou total é recomendada quando o tratamento clínico com antiprogestágeno falha ou, em casos de sepse, ulceração extensa e necrose, como nos pacientes deste relato.(AU)

Severe mammary fibroepithelial hyperplasia due to single injection of medroxyprogesterone acetate in two male cats / Hiperplasia fibroadenomatosa mamária felina secundária à aplicação única de acetato de medroxiprogesterona em dois felinos machos

ABSTRACT: Thirty and forty days after a 50 mg medroxyprogesterone acetate injection, respectively, two mixed-breed, 7 and 8-month-old entire male cats presented diffuse enlargement of thoracic and abdominal mammary glands, with ulceration, abscessation and necrosis. One patient was treated with 10 mg/kg aglepristone, antibiotic therapy, analgesic and non-steroidal anti-inflammatory compound; however a worse enlargement of mammary glands, necrosis and clinical condition was noted two days after antiprogestin injection. The second patient was submitted to surgical procedure without previous medical treatment. A partial bilateral mastectomy and conventional orchiectomy were performed, and both patients presented no clinical abnormalities 10 days after surgical treatment. In the male cat, the interruption of progesterone associated mammary fibroepithelial hyperplasia cannot be based in gonadectomy, being antiprogestin treatment the primary approach. Mastectomy can be a treatment option in selected cases, such as the two cases presented here, in case of antiprogestin treatment failure or in case of extensive ulceration, necrosis and risk of sepsis.

RESUMO: Trinta e quarenta dias após aplicação de acetato de medroxiprogesterona, dois gatos SRD machos não castrados, de sete e oito meses respectivamente, apresentaram aumento difuso de volume em glândulas mamárias torácicas e abdominais, com ulceração, abscedação e necrose. Um paciente foi tratado com 10 mg/kg de aglepristone, terapia antimicrobiana, analgésicos e anti-inflamatório não-esteroidal. Entretanto, apresentou piora dos sinais clínicos, da abscedação e necrose dois dias após a aplicação. O outro paciente foi submetido a procedimento cirúrgico sem tratamento clínico prévio. Mastectomia parcial bilateral e orquiectomia convencional foram realizadas e, ambos os pacientes se apresentaram sem alterações clínicas e receberam alta após 10 dias do procedimento cirúrgico. No felino macho, a interrupção da ação da progesterona associada à ocorrência de hiperplasia fibroadenomatosa mamária, não pode ser obtida por meio de gonadectomia, portanto, o tratamento de eleição deve ser realizado com utilização de antiprogestágeno. Em alguns casos, mastectomia parcial ou total é recomendada quando o tratamento clínico com antiprogestágeno falha ou, em casos de sepse, ulceração extensa e necrose, como nos pacientes deste relato.

Increased High Molecular Weight FGF2 in Endocrine-Resistant Breast Cancer.

Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.

Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters.

There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.

Associação da acupuntura e aglepristone no tratamento de hiperplasia mamária em gata / Association of acupuncture and aglepristone in treatment of mammary hyperplasia in cat

Backgroun d: Feline mammary hyperplasia is a nonneoplastic condition characterized by a rapid hypertrophy and hyperplasia of stroma and ductal epithelium of mammary glands due to hormonal stimuli. This condition is frequently seen in young female cats and is associated with an increase in serum endogenous progesterone or application of exogenous progestogen used as contraceptive. The present study aimed to describe a case of feline mammary hyperplasia treated with the association of aglepristone and acupuncture. Case : A female cat was attended at Hospital de Clínicas Veterinárias of Universidade Federal do Rio Grande do Sul presenting a history of increasing mammary volume after a single progestogen injection. The contraceptive administration was made by the patient owner due to signs of her first estrus and starting mammary development after this application four days ago. The patient had a generalized increase in breast, with solid consistence and high temperature. The ovariectomy was performed through the flank and, 24 days after surgery, had not been seen any mammary reduction, it was decided to aglepristone administration at 10 mg/kg subcutaneously, once a day, for three consecutive days. Acupuncture was performed once or twice a week, stimulating the acupuncture points Yintang, SP6, ST36, ST40, GV14, GV20, GV24, LIV2, LIV3, LIV13, LIV14, CV4, CV8, CV10, CV17, BL23 and LI4, that have, among other indications, analgesic, anti- inflammatory, soothing and immune stimulant actions. Tissue involution had began after antiprogestin applications and some acupuncture sessions. However, there was formation of an abscess in breast that prevents further tissue remission and was only detected after fistulation, delaying patient recovery. After abscess content drainage there was a significant mammary volume reduction and restoration of breast normal size occurred in seven days. Discussion : The patient had received one exogenous progestogen injection and was presenting generalized mammary in - crease, symmetrically and bilaterally, with solid consistence and high temperature, allowing the achievement of a diagnosis based on history and clinical signs. The patient was treated surgically by ovariectomy performed through the flank due to the oversized mammary glands, removing endogenous source of progesterone and preventing the recurrence of disease, as recommended by several authors. Aglepristone, that acts by blocking progesterone receptors, was administered at a dose of 10 mg/kg as recommended by manufacturer and aimed to accelerate mammary volume reduction. This antiprogestin has been indicated by literature when surgical treatment is not effective. During aglepristone action the patient was sub - mitted to acupuncture sessions with intention of accelerate mammary tissue regression and healing process and improve her immunity. Among several indications of acupuncture, it is reported the promotion of analgesia, immune modulation and activation of regenerative processes, which occur due to release of chemicals and neuropeptides as a result of nervous system stimulation. The association of aglepristone with acupuncture was effective in mammary hyperplasia treatment because, despite an abscess formation at the site, there was a rapid mammary involution after drainage of purulent content.(AU)

Associação da acupuntura e aglepristone no tratamento de hiperplasia mamária em gata / Association of acupuncture and aglepristone in treatment of mammary hyperplasia in cat

Backgroun d: Feline mammary hyperplasia is a nonneoplastic condition characterized by a rapid hypertrophy and hyperplasia of stroma and ductal epithelium of mammary glands due to hormonal stimuli. This condition is frequently seen in young female cats and is associated with an increase in serum endogenous progesterone or application of exogenous progestogen used as contraceptive. The present study aimed to describe a case of feline mammary hyperplasia treated with the association of aglepristone and acupuncture. Case : A female cat was attended at Hospital de Clínicas Veterinárias of Universidade Federal do Rio Grande do Sul presenting a history of increasing mammary volume after a single progestogen injection. The contraceptive administration was made by the patient owner due to signs of her first estrus and starting mammary development after this application four days ago. The patient had a generalized increase in breast, with solid consistence and high temperature. The ovariectomy was performed through the flank and, 24 days after surgery, had not been seen any mammary reduction, it was decided to aglepristone administration at 10 mg/kg subcutaneously, once a day, for three consecutive days. Acupuncture was performed once or twice a week, stimulating the acupuncture points Yintang, SP6, ST36, ST40, GV14, GV20, GV24, LIV2, LIV3, LIV13, LIV14, CV4, CV8, CV10, CV17, BL23 and LI4, that have, among other indications, analgesic, anti- inflammatory, soothing and immune stimulant actions. Tissue involution had began after antiprogestin applications and some acupuncture sessions. However, there was formation of an abscess in breast that prevents further tissue remission and was only detected after fistulation, delaying patient recovery. After abscess content drainage there was a significant mammary volume reduction and restoration of breast normal size occurred in seven days. Discussion : The patient had received one exogenous progestogen injection and was presenting generalized mammary in - crease, symmetrically and bilaterally, with solid consistence and high temperature, allowing the achievement of a diagnosis based on history and clinical signs. The patient was treated surgically by ovariectomy performed through the flank due to the oversized mammary glands, removing endogenous source of progesterone and preventing the recurrence of disease, as recommended by several authors. Aglepristone, that acts by blocking progesterone receptors, was administered at a dose of 10 mg/kg as recommended by manufacturer and aimed to accelerate mammary volume reduction. This antiprogestin has been indicated by literature when surgical treatment is not effective. During aglepristone action the patient was sub - mitted to acupuncture sessions with intention of accelerate mammary tissue regression and healing process and improve her immunity. Among several indications of acupuncture, it is reported the promotion of analgesia, immune modulation and activation of regenerative processes, which occur due to release of chemicals and neuropeptides as a result of nervous system stimulation. The association of aglepristone with acupuncture was effective in mammary hyperplasia treatment because, despite an abscess formation at the site, there was a rapid mammary involution after drainage of purulent content.