Bcl-2 expression and prognostic significance in feline invasive mammary carcinomas: a retrospective observational study.

BACKGROUND: Cats spontaneously develop invasive mammary carcinomas with high clinical aggressiveness, and are considered relevant animal models for human breast cancer. Bcl-2 is an anti-apoptotic pro-survival protein, whose expression is associated with a favorable outcome in human breast cancer. The aim of our study was to determine the frequency of Bcl-2 expression in feline invasive mammary carcinomas (FMCs), its relationship with other clinicopathologic variables, and its prognostic value. This retrospective study included 180 FMCs, diagnosed in female cats treated by surgery only, with a 2-year follow-up post-mastectomy. Bcl-2, ER, PR, Ki-67, HER2, and CK5/6 expression were determined by automated immunohistochemistry. A receiver-operating-characteristic curve was used to set the threshold for Bcl-2 positivity. RESULTS: The cohort comprises 32% (57/180) luminal FMCs defined by ER and/or PR positivity, and 68% (123/180) triple-negative FMCs (negative for ER, PR, and HER2). Bcl-2 expression was considered as positive when at least 65% of tumor cells were immunohistochemically stained. Thirty-one out of 180 FMCs (17%) were Bcl-2-positive. There was no significant association between Bcl-2 expression, and the tumor size, nodal stage, histological grade, or ER, PR, Ki-67, HER2, and CK5/6 expression. By multivariate survival analysis (Cox proportional-hazards regression), Bcl-2 positivity in FMCs was associated with longer disease-free interval (p = 0.005, HR = 0.38), overall survival (p = 0.028, HR = 0.61), and cancer-specific survival (p = 0.019, HR = 0.54) independently of other powerful prognostic factors such as pathologic tumor size, pathologic nodal stage, and distant metastasis. The positive prognostic value of Bcl-2 was confirmed in both luminal FMCs, of which 9/57 (16%) were Bcl-2-positive, and in basal-like triple-negative (ER-, PR-, HER2-, CK5/6+) FMCs, of which 14/76 (18%) were Bcl-2-positive. CONCLUSIONS: Compared to human breast cancer, Bcl-2 positivity in feline invasive mammary carcinomas is also associated with better outcome, but is less common, and not associated with ER, PR, and HER2 expression. Cats with spontaneous Bcl-2-positive FMCs could be useful in preclinical trials evaluating anti-Bcl-2 strategies for chemoresistant luminal or triple-negative breast cancers.

Failure of lower motor neuron radial outgrowth precedes retrograde degeneration in a feline model of spinal muscular atrophy.

Feline spinal muscular atrophy (SMA) is a fully penetrant, autosomal recessive lower motor neuron disease in domestic cats that clinically resembles human SMA Type III. A whole genome linkage scan identified a ∼140-kb deletion that abrogates expression of LIX1, a novel SMA candidate gene of unknown function. To characterize the progression of feline SMA, we assessed pathological changes in muscle and spinal cord from 3 days of age to beyond onset of clinical signs. Electromyographic (EMG) analysis indicating denervation occurred between 10 and 12 weeks, with the first neurological signs occurring at the same time. Compound motor action potential (CMAP) amplitudes were significantly reduced in the soleus and extensor carpi radialis muscles at 8-11 weeks. Quadriceps femoris muscle fibers from affected cats appeared smaller at 10 weeks; by 12 weeks atrophic fibers were more prevalent than in age-matched controls. In affected cats, significant loss of L5 ventral root axons was observed at 12 weeks. By 21 weeks of age, affected cats had 40% fewer L5 motor axons than normal. There was no significant difference in total L5 soma number, even at 21 weeks; thus degeneration begins distal to the cell body and proceeds retrogradely. Morphometric analysis of L5 ventral roots and horns revealed that 4 weeks prior to axon loss, motor axons in affected cats failed to undergo radial enlargement, suggesting a role for the putative disease gene LIX1 in radial growth of axons.